The potential mechanisms of action of nongenotoxic tumor promoting and carcinogenic compounds have been studied in rat and mouse liver. Nongenotoxic chemicals may induce tumors in chronic toxicology experiments by enhancing spontaneous carcinogenesis. Two experimental models were developed in aging F344 rats and C3H mice to study the effects of nongenotoxic chemicals on spontaneous hepatocarcinogenesis. All agents studied, including phenobarbital, did not accelerate progression of naturally occurring preneoplastic or neoplastic lesions. Instead phenobarbital appeared either to induce a morphologically distinct population of preneoplastic hepatocellular foci that, in turn, developed into tumors or to promote spontaneously initiated hepatocytes into preneoplastic lesions and tumors. These findings are in marked contrast to those after phenobarbital exposure in initiated rats, whereby the major effect of phenobarbital is to enhance growth of preneoplastic and neoplastic lesions into carcinomas. These studies should help define mechanisms of action of nongenotoxic compounds. In related studies, a model of chronic hepatic hyperplasia is being developed in mice. Levels of DNA synthesis, thymidine kinase and other biochemical parameters are evaluated in relation to hepatic histopathology and organ weights. The chronic hyperplasia induced in liver or kidney may be independent of any carcinogenic effect of a nongenotoxic chemical.